The capability to analyze cellular signal transduction pathways with increasing sensitivity and temporal resolution plays a key role in understanding the underlying molecular pathways involved in human diseases and disorders. Among the most challenging analytes are those present at very low concentrations with high temporal variability and small molecules lacking moieties amenable for optical and/or electrochemical detection. Radioisotopic labels play key roles in the investigation of biological systems in both the research and clinical environments, particularly for small molecule signals derived from carbohydrates. Radioisotopes facilitate highly sensitive detection with minimal perturbation of the analyte, compared to fluorescent labels, etc. Beta-particle emitters, including 32P, 35S, 14C and 3H are commonly used as biological tracers due to the prevalence of these atoms in biological molecules. The most universal radioisotopic label is 3H, due to the ubiquitous presence of H in molecular systems. 3H possesses a number of inherent advantages, including low mass differences between labeled and unlabeled compounds, a reasonable half-life for storage and low energy and short penetration depth that make 3H the safest b-emitting isotope commonly used for biological analysis. Unfortunately, the low energy and short penetration depth also complicate detection of 3H compared to other radioisotopes, minimizing the ability to analyze dynamic signaling processes in single cells or small groups of cells. We propose to develop and characterize a novel core-shell nanomaterial, termed nanoSPA, functionalized with scintillating dyes for sensitive detection of low energy radioisotopes in intracellular environments. This nanomaterial is prepared by depositing a thin silica shell onto a polymer core that is doped with radioisotope- responsive scintillants. The polymer matrix facilitates energy absorption and transfer from the radioisotope to the scintillant dye, whereas addition of the silica shell increass solubility in aqueous samples, and provides an easily modified surface. nanoSPA presents a number of advantages compared to existing technologies, including: a) enhanced compatibility with aqueous samples; b) a high-surface area to volume (SA/V) ratio for improved SPA; c) an easily modified surface for attachment of biomolecules and other chemical species; and d) applicability for intracellular radioisotope imaging. The nanoSPA platform that is proposed herein will provide a key enabling technology in a wide range of applications relevant to human health. Though we will focus our initial, proof-of-concept efforts on assays relevant to glucose-regulated insulin secretion, the range of applications for this technology is extremely broad.